Therapy for Early-Stage Colorectal Cancer

Therapy for Early-Stage Colorectal Cancer

Drs. Peeters and Haller provide a thorough review of the recent
historical development, current state of knowledge, and future of
adjuvant therapy for early-stage colon and rectal cancers. They
provide reasonable recommendations for the management of patients
with colon or rectal carcinoma that are based on the results of
published clinical trials.

The authors point out that, for patients with colon and rectal
cancer, there exist differences in survival that correlate with the
pathologic stage (widely thought to be the most important prognostic
indicator). Furthermore, they emphasize the importance of differences
in the natural history of the two diseases and describe how these
differences affect the clinicians approach to preventing
recurrence (eg, rectal cancers require aggressive local control since
local failures are common).

Peeters and Haller conclude that all stage III patients should be
offered treatment with either 1 year of fluorouracil (5-FU) plus
levamisole (Ergamisol) or 6 months of 5-FU plus folinic acid. This
conclusion is based on the results of the second intergroup study
(INT-0089), which compared four treatment groups (5-FU + low-dose
folinic acid ± levamisole administered for a total of 6 months
and 5-FU + high-dose folinic acid ± levamisole administered for
12 months); the National Surgical Adjuvant Breast and Bowel Project

The authors make no comments concerning their preference for low- vs
high-dose folinic acid. This is understandable, since at least seven
randomized trials comparing high- and low-dose folinic acid regimens
have yielded conflicting results.[1] Most of these trials have found
either a trend for superior benefit with high-dose folinic acid or at
least equivalent efficacy of the high- and low-dose regimens.

Preclinical pharmacokinetic studies support the use of high-dose
folinic acid even while the ambiguous results from clinical trials
seem to imply equivalency between the two regimens (at least in terms
of benefit).[2] Toxicity analyses from these studies are also
conflicting. Some researchers report varying spectra and higher
overall treatment-related toxicities with low-dose folinic acid,
while others reach similar conclusions about the high-dose regimens.

Recent Analysis of NSABP Trials

The NSABP recently concluded a comparison of results in patients with
Dukes stage B or C colon cancer treated with postoperative
adjuvant therapy on NSABP trials (C-01, C-02, C-03,C-04) from 1977 to
1990.[3] The patient populations were remarkably similar, since the
eligibility criteria and follow-up requirements were comparable.

In all four studies, an overall improvement in disease-free survival
and recurrence-free survival improvement was noted for all patients
with either Dukes stage B or C disease. When the relative
efficacy of chemotherapy was examined within stage, there was always
an observed reduction in mortality, recurrence, or disease-free
survival from chemotherapy, irrespective of stage. Furthermore, in
most cases, the reduction was as great or greater for Dukes
stage B patients than for Dukes stage C patients. This was true
for each individual trial and also when data from all four trials
were examined in a combined analysis (a 31% mortality reduction in
Dukes stage B patients occurred irrespective of the presence or
absence of adverse prognostic factors).

As alluded to by Peeters and Haller, the nonsignificant, 32%
reduction in recurrence (P = .10) in INT 0035 may be explained by the
fact that the study did not have sufficient statistical power to
detect reductions in recurrence of less than 50%. For this reason, in
terms of recurrence, the results of the NSABP cross-study analysis
and those of INT 0035 are not discordant.

Likewise, although there was no difference in overall survival in the
treatment groups in INT 0035, there was a nonsignificant, 20%
reduction in the rate of colon cancerrelated deaths in the
group receiving 5-FU + levamisole.[4] It is likely that the lack of
an overall survival benefit was due to the relatively high
noncancer-related death rate among the Dukes stage B patients.

Even if the predicted absolute 5-year survival advantage is small for
Dukes stage B patients, the abbreviated duration of adjuvant
therapy (6 months), the emergence of effective oral adjuvant
therapies (uracil/tegafur [UFT] + folinic acid [Orzel]), the dire
consequences of recurrence, and the lack of correlation with
identified adverse prognostic factors lead me to conclude that, at
this time, all Dukes stage B patients should be offered
adjuvant therapy. In the future, as more reliable predictors of
prognosis and relapse become apparent, subsets of Dukes stage B
patients may be identified, which will allow us to further refine
this recommendation.

Treatment of Early Rectal Cancer

I agree with the authors recommendations concerning the
treatment of early rectal cancer. Questions regarding the timing and
duration of radiation therapy, the use of preoperative or
postoperative radiation therapy, combined-modality therapy with
chemotherapy and radiation, and the ability of these manipulations to
improve sphincter preservation, local control rate, disease-free
survival, and overall survival are far from definitively answered.

The current Dutch (CKVO 95-04) and Scandinavian trials are designed
to answer the questions of whether

short-course radiotherapy prior to surgery offers a local control and
survival advantage, and whether postoperative 5-FUbased
chemotherapy adds additional benefit for patients with Dukes
stage B or C disease.[5,6]

In addition, one American randomized trial that is currently accruing
patients (NSABP protocol R-03) is comparing preoperative and
postoperative combine- modality therapy in this population of
patients. (Another American trial was terminated early due to a lack
of accrual). The primary end points of R-03 are to determine
disease-free survival and overall survival in patients treated with
preoperative combined-modality therapy, but important information
will also be obtained concerning tumor downstaging, local recurrence
rates, sphincter preservation, and primary tumor response rate.

A preliminary report of this study indicates that sphincter-sparing
rates may be lower than expected.[7] At present, this study is also
accruing patients slowly, and steps are being taken to encourage a
larger accrual and to expand the population sampled. Until the
results of R-03 are available, it is safe to say that the roles of
preoperative or postoperative combined-modality therapy will remain uncertain.

Summary

The article by Peeters and Haller represents a thorough, yet concise
review of the treatment of patients with early colon and rectal
cancers. The authors offer treatment recommendations based on the
results of current clinical trials that are widely accepted as
credible. They also briefly review the possible roles of new
treatment modalities and chemotherapeutic agents that will likely be
available shortly as part of the routine treatment armamentarium.

Their treatment of these complex data is balanced and well-founded.
With the exception of an admittedly debatable disagreement about the
treatment of Dukes stage B colon cancer patients, I found this
review to be useful and timely.

It is important to remember that, in the absence of randomized
trials, clinical experience is all that treating physicians have to
rely on to determine the best treatments for their patients. Peeters
and Haller do an admirable job of interpreting pertinent clinical
trials to the full extent possible, arriving at judicious conclusions
(and acknowledging the limitations of those conclusions), and then
using these conclusions to make practical recommendations for treatment.